PHARMACEUTICAL COMPOSITION CONTAINING 5-MORPHOLINOMETHYL-3-(4-CHLOROBENZYLIDENEAMINE)-2-OXAZOLIDINONE AND ITS USE FOR THE TREATMENT OF CNS DISORDERS

Abstract: A pharmaceutical composition, containing as active substance 5-morpholinomethyl-3-(4-chlorobenzylideneamine)-2-oxazolidinone of formula (I) and/or pharmaceutically acceptable salt thereof together with pharmaceutically acceptable carriers and optionally auxiliary agents and the use of 5-morpholinomethyl-3-(4-chlorobenzylideneamine)-2-oxazolidinone for the preparation of a medicament having central nervous system activities are disclosed.

Description: PHARMACEUTICAL COMPOSITION CONTAINING 5-MORPHOLINOMETHYL-3-{4- CHLOROBENZYLIDENEAMINE)-2-OXAZOIJDINONE AND ITS USE FOR THE TREATMENT OF CNS DISORDERS The present invention relates to the pharmaceuti¬ cal composition, posessing psychotropic and especially anti-depressive activity, which can be used in the treatment of the central nervous system diseases and its functional disorders. Psychotropic drugs known for their effects on the cen¬ tral nervous system are applicable in the therapy of psychi- cal disorders and as assisting drug in the treatment of other systems. According to their application the psychotro¬ pic drugs fall into five classes: neuroleptics, tranquili- sers, anxiolytics, anti-depressants and nootropics. Depres¬ sion affects in a varying degree ca 6% of the population. It is the result of interaction between the negative factors of the environment (stress) and the individual biochemical sus¬ ceptibility, which is genetically conditioned. The biochemi¬ cal basis for depression is related to the abnormal level of monoamines in the brain, particularly noradrenaline and se- rotonin (5-hydroxytryptamine) . Hence the therapy of de¬ pression is focused on the question of increasing the level of monoamines in the brain. Very frequently applied i.n the therapy of depression are tri- and tetracyclic drugs. They produce an effect on wide range of neurotransmitters, inclu- ding noradrenaline, serotonin, dopa ine, histamine and ace- tylocholine. However, these drugs, due to their multidirec¬ tional action, have a number of side effects and can also cause an addiction. In the therapy of depression nonccmpeti- tive monoamine oxidase (MAO) inhibitors have been app] Led as well. MAO inhibitors, however, cause some metabolism distur¬ bances of monoamines taken with food. This is why thf-ir ap¬ plication is reduced to the cases which do not reac to other drugs. The significant progress was the introduction of new serotonin re-uptake inhibitors . Their characteristic; fe- ature is high effectiveness and a smaller number of side ef¬ fects. The chemical structure of these drugs considerably differs from the classical tri- and tetracyclic anti-depres¬ sants. A new drugs with anti-depressive effect has been sear¬ ched in different chemical classes. In the patent application nr DE 4005371 the derivatives of N-aryl-2-piperidinoethyl-2-oxazolidinone and the phar¬ maceutical compositions containing them were disclosed. It was stated that those agents showed the effect on the cen¬ tral nervous system, particularly sedative, tranqulising, neuroleptic and anti-depressive effects. The derivatives of 3-aryl-4-piperidinoalkil-2-oy=ιzoli- dinone and pharmaceutical compositions containing them are known from the european patent application nr EP 459256. They show central nervous system activity, particularly se¬ dative, tranquilising, neuroleptic and anti-depressive ac¬ tivity. According to the invention there is provided a pharma- ceutical composition, which contains as the active substance 5-morpholinomethyl-3-(4-chlorobenzylideneamine)-2-oxazolidi- none of formula I and/or pharmaceutically acceptable salt thereof and a phar¬ maceutically acceptable carrier and optionally at least one auxilliary substance. The pharmaceutical composition according to the inven¬ tion contains an active substance in its free form or Ln the form of pharmaceutically acceptable salt, particularly acid addition salt. These can be salts with inorganic acids, such as hydrochloric, hydrobromic, phosphoric acid and organic acids, such as for example formic, acetic, propionic, malo- nic, citric, lactic, tartaric, gluconic, nicotinic, methane- or ethanesulphonic, ascorbic, naphthalenesulphonic and fuma- ric acid. In the preferred embodiment the pharmaceutical composi¬ tion according to the invention contains as the active su- bstance 5-morpholinomethyl-3-(4-chlorobenzylideneamine)- 2-oxazolidinone hydrochloride. In further aspect the present invention relates to the use of 5-morpholinomethyl-3-(4-chlorobenzylideneamine)-2- oxazolidinone of formula I given above or pharmaceutically acceptable salt thereof for the preparation of a medicament having central nervous system activity. In another aspect the present invention relates ~o the method of treatment of central nervous system diseases and disorders which comprises the administration to a person suffering from such disease or disorder a therapeutically effective amount of 5-morpholinomethyl-3-(4-chlorobenzyli- deneamine)-2-oxazolidinone of formula I given above and or pharmaceutically acceptable salt thereof. The daily dosage of the 5-morpholinomethyl-3-(4-chlo- robenzylideneamine)-2-oxazolidinone applied for the therapy of the central nervous system, especially depression, ranges between 1 to 10 mg/kg body weight and depends on the mode of administration. 5-Morpholinomethyl-3-(4-chlorobenzylideneamine)-2-oxa- zolidinone can be obtained by the condensation of 5-morpho- linomethyl-3-amine-2-oxazolidinone with 4-chlorobenzaldehyde in water-alcohol solution and acidic environment (pK 5-6) , as described by A.Swirska in Acta Polon. Pharm. 19, 3/7, 324, 1962. Acid addition salts can be obtained by conventio- nal methods, well known to a person skilled in the art, The compositions according to the invention may be in any form of dosage units known in the pharmaceutical practi¬ ce, for instance as described in "Remington's Pharmaceutical Sciences, 18th edition, Mac Publishing Co., 1990. It can be the form for oral administration, for example tablet, ca¬ psule, powder, granules, syrup, parenteral form, such as sterile solution or emulsion, for example water or oil so¬ lution and emulsion for injections or infusions, or free- ze-dried powder for reconstitution ex tempore. They can also have form of suppositories for rectal administration. The compositions may contain conventional organic or inorganic carriers, typically used in pharmaceutical techno¬ logy, chosen depending on the required form of the composi¬ tion. Suitable carriers include for instance water, vegetab- le oils, benzyl alcohol, polyethylene glycol, gelatine, car¬ bohydrates, such as for instance starch and starch derivati¬ ves, cellulose and cellulose derivatives, lactose, magnesium stearate, talc, etc. The Compositions according to the invention can contain auxiliary substances such as for example preservatives, sta¬ bilizers, buffers, emulsifiers, solubilizers, salts regula¬ ting osmotic pressure, binders, lubricants, glidants, iisin- tegrants, coloring agents, flavoring agents, all of them ap¬ plied according to the form and need. Solid oral forms can be obtained by procedures well-known from pharmaceutical practice. For instance tab¬ lets can be made either by means of conventional methods of mixing and direct compressing into tablets or tabletting with preceding granulation. Tablets can be covered with pa- renteral coating, resistant against the action of gastric juice or regulating the absorption time of active substance. Liquid oral forms can be obtained by dissolving or sus¬ pending the active substance in water or other solvents tog- hether with conventional auxiliary agents, for instance fla- vours. Such preparations can be also in dry form which is dissolved directly before use. • Forms for parenteral administration are produced from the active substance and sterile vehiculum. The solutions are obtained by dissolving the active substance in liquid medium, sterile filtration and sealing. Auxiliary substances also can be dissolved in the liquid medium. For prolonging the preparation stability the mixture in the ampoule can be freze-dried. The suspensions for parenteral administration are obtained generally in the same way. However, the active substance instead of being dissolved is suspended in a li¬ quid carrier. Additional agents for keeping the active su¬ bstance homogenous are possible. In that case sterilisation is not obtained through the process of filtration. The results of pharmacological examinations Materials and methods The experiments were conducted on mice, both sexes, of the Balb/c and outbred Ipf:M/2 strain (20-40 g) , male rats of the Wistar and outbred Ipf:R/2 strain (160-240 g) . The preparations were administered per os (p.o.) in the form of 5% carboxymethylcellulose suspension or intraperitoneally (i.p.) in the form of water solutions and steady volumes: mice 0,1 ml/10 g i.p. or 0,2 ml/10 g p.p.; rats 0,2 ml/100 g i.p. or p.o.. Control animals were given a solvent in the corresponding way. The statistic evaluation of the results was made by means of t-Student test. 1) The influence on the rats behaviour in "despair test". The experiment was conducted according to the method described by Porsolt in Eur. J. Pharmacol., 1978, 47, 379. The rats were placed separately in upright, metallic cylin- drical containers, 60 cm high and 18 cm in diameter, contai¬ ning 15 centimeters of water, in the temperature 25°C. After 15 minuts the animals were taken from the containers, dried and put to cages. After 24 hours the rats were dived in wa¬ ter again and for 5 minutes the complete immobility period was measured. The examined preparation (containing 5~mor- pholinomethyl-3-(4-chlorobenzylideneamine)-2-oxazolidinone hydrochloride or imipramine (IMI) were administered per os twice: 24 hours and one hour before the beginnning of the observation. The result is presented in Table 1. Table l: The effect on the rats behaviour in "despair test" Tne number of animals in the group = 8 * p<0,01 The examined preparation administered in the dosage of 200 mg/kg shortened the rats' immobility period by 18% in relation to the control group. The effect equals approxima¬ tely to the effect of IMI (20 mg/kg) applied in the similar way. 2) The intensification of L-Dopa effects in reserpine pret- reated mice. The examined preparation was administered to mice p. o. in the dosages of 40 and 200 mg/kg 17 hours after reserpine in the dosage of 2,5 mg/kg had been administered intra- peritoneally. After one hour L-dopa was injected in the do¬ sage of 300 mg/kg. The intensification of L-dopa anti-reserpine action was evaluated according to the follo¬ wing parameters of the animals behaviour: mobility, irrita- bility, ptosis and body temperature. According to the same empirical system IMI was examined in the dosages of 8 and 40 mg/kg. The results are presented in Table 2. Table 2: The intensification of L-dopa effects in reserpine pretreated mice. It was found that the examined preparation intensified the- behavioural effects of L-dopa action in reserpine pret¬ reated mice in the same way as IMI. It reduced ptosis and hypothermy and raised the animals' mobility and irritabili- ty. A smaller dosage proved to be more effective than a big¬ ger one. After 200 mg/kg had been applied, a distinct two-phase action of the examined preparation was observed. In the first hour after the application it came to the loss of body posture (righting) reflex. After 90 minutes there appeared irritability and big incitement, which lasted over an hour. 3) The intensification of L-dopa effects in mice premedica- ted with pargyline. Three hours after the oral administration of pargyline in the dosage of 40 mg/kg, the " were applied orally ≥ither the examined preparation or IMI, followed one hour after by L-dopa administered intraperitoneally in the dosage of 200 mg/kg. The behaviour of the mice was evaluated according to the following 5-level score: 1 - piloerection, Straub,s tail, exophtalmos of eyes, minute salivating, irritability. 2 - as above + translocations, single jumps. 3 - as above + bigger incitement of mobility, frequent jumps, climbing, single squeaks. 4 - as above + great incitement of mobility, aggresion, fights. 5 - as above + maximum incitement of mobility and aggresion The results are presented in Table 3. Table 3: The intensification of L-dopa effects in mice pre- medicated with pargyline Dosage Reaction of mice according Preparation mg/kg p.o. to score Control 1 - 2 Examined 10 5 preparation 20 5 40 5 200 3 - 4 IMI 4 4 40 3 - 4 The number of animals in the group = 8. The examined preparation proved very strong intensifi¬ cation of L-dopa effects in mice premedicated with pargyli¬ ne. The strongest mobility and emotion incitement was obser¬ ved after the dosages of 10, 20 and 40 mg/kg. The examined preparation shows in this test stronger effectiveness than IMI. 4) The influence on the concentration of beta-adrenergic ce¬ rebral receptors in vivo. Rats were administered the examined preparation in the form of intraperitoneally injection and the dosage of 200 mg/kg twice daily for six weeks. In the same empirical sys¬ tem IMI was examined in the dosage of 10 mg/kg. The animals were killed 24 hours after the last injection and their ce- rebral cortexes were skeletonized. The population of the beta-adrenergic receptor was cha¬ racterised by the examination of the parameters of the 3 H-dihydroalprenolol ( 3 H-DHA) bonding to the membranes (fractiom P 2 ) of the cerebral cortex. The tissue was homoge- nised in 20 volumes of the 50 mM buffer TRIS-HCl, pH 7,6, in the Polytron disintegrator (position 4,155) and centrifuged at lOOOg for 10 minutes. The supernatant was decanted and again centrifuged at 25000 for 20 minutes. The operations were conducted in the temperature of 0-4°C. The precipitate, after the second centrifugation, decanting and removing the supernatant, was kept in the temperature of -18°C until the time of incubation (no longer than 48 hours) . The final fraction P 2 was obtained by the subsequent process of the sediment homogenisation in such a volume of 50 mM buffer TRIS-HCl, pH 7,6, that the final concentration of protein amounted to 1,5 mg/ml. The incubation mixture, containing 450 μl of the frac- tion P 2 suspension, 50 μl of the H-DHA solution (6 diffe¬ rent solutions; the final concentrations in the mixture 0,05-3 mmol/litr) and 50 μl of buffer or propranolol solu¬ tion (the final concentration in the sample 10 μl/litr) was incubated for 30 minutes in the temperature of 25°C. The in¬ cubation was finished by filtrating the suspension through filters made of glass fibres. The filters were twice rinsed with 5 ml of cold (0°C) buffer TRIS-HCl, pH 7,6, and placed in scintillation minivessels, to which Bray's liquid was ad¬ ded. The radioactivity was measured by the Packard scintil¬ lation counter, model B329 with the efficiency of 36-37%. The specific bonding was defined as the radioactivity difference between the samples incubated in the absence of propranolol (complete bonding) and in the presence of 10 μM of propranolol (blank) . The data from the counter (cp ) were recalculated individually into the decay frequence (dpm) , calculating it from the individual efficiency of each sam- pie, received from the relation of impulses in the canals A and B. B max value and the constant of dissociation K D was calculated from the Scatchard diagrams, which were rectili¬ near. The results are presented in Table 4. Table 4: The effect of the chronic administration of the examined preparation or IMI on the 3 H-alprenolol bonding to the membranes of a rats' cerebral cortex. Prepar. daily N 1 B max K D dosage fmole/mg protein % nmol/litre % mg/kg X ±SEM X ±SEM Control 29 134,2 ±11,7 100 1,94 ±0,24 100 IMI 23 80,8 ±8,23 60 2,05 ±0,28 129 Examined prepara¬ tion 40 29 89,4 6,91 67 1,23 0,18 63 200 24 96,4 7,67 72 1,31 0,13 68 F(df 3/K 31) 7,44 (p<o,oooι; 1 3,84 (p<0,05) total number of points (average number from two operations) used for fixing the B maχ and K D values. The X and SEM values were calculated by means of regression analysis. The administration of the preparations caused a consi¬ derable decline of the concentration of beta-adrenergic re¬ ceptors. The effects of imipramine or both dosages of the exami¬ ned preparation on the concentration of receptors did not differ considerably. As distinct from imipramine, the chro¬ nical administration of the examined preparation in both dosages caused a statistically considerable decline of the constant of dissociation value K D and consequently the in¬ crease of the beta-adrenergic receptor affinity. 5) The effect on the uptake of monoamines in vivo. The point of reference for measuring the inhibiting ef¬ fect on the uptake of noradrenaline was the protection from the effect of 6-hydroxydopamine (6-OHDA) , which was adminis¬ tered intraventricularly. Rats were applied intraventricu- larly 250 μg of 6-OHDA in the volume of 20 μl of 0,9% solu¬ tion of HC1 and 0,1% solution of ascorbic acid. One hour be- fore the 6-OHDA application the rats were administered IMI in the dosage of 20 mg/kg or the examined preparation in the dosages of 40 or 400 mg/kg. The animals were decapiteted 7 days after and the level of noradrenaline in the whole brain was measured by the division on the Sephadex G-10 column and fluorimetric assay following oxidation. The results are pre¬ sented in Table 5. Table 5. The effect of the examined preparation and IMI on the uptake of noradrenaline in vivo. Concentration of noradrenaline in the brain (mg/kg tissue) Group X ±SEM % in relation to the group after chemosympathectomy Control 205 ±10,5 (10) 216 6-OHDA 95 ±6,9 (10) 100 IMI, 20 before 6-OHDA 179 ±13,5 (9) 188 Examined preparation 200 before 6-OHDA 148 ±24,9 (8) 155 40, before 6-OHDA 88 ±14,3 (10) 92 F (4/42 13,55 (p<0,0001) It was observed that 6-OHDA administered intraventricu- larly causes a considerable (over 50%) decline of the norad- renalin content in the cerebrum. A low dosage of the exami- ned preparation does not prevent the effect of 6-OHDA com¬ pletely. However, the higher dosage inhibits it almost as effectively as IMI. Concluding, the examined preparation, applied in high dosages, proves effective in inhibiting the uptake of noradrenaline. The point of reference for measuring the inhibitory ef¬ fect on the uptake of serotonin was the protection from the effect of intraperitoneally applied p-chloramphetamine. p-Chloramphetamine in the dosage of 10 mg/kg was administe¬ red 60 minutes after citalopram in the dosage of 20 mg/kg or the examined preparation in the dosage of 400 mg/kg had been applied for confrontation. The animals were decapitated three hours later and the level of serotonin was measured by means of the same procedure as the level of noradrenalin. The results are presented in Table 6. Table 6. The effect of examined preparation and citalopram on the uptake of serotonin in vivo. Concentration of noradrenaline in the brain (mg/kg tissue) Group X ±SEM % in relation to (dosage in mg/kg) the group after p-chloramphetamine Control 353 ±17,7 ( 9) 169 p-CA 213 ±9,7 (10) 100 Citalopram (20) before 6-OHDA 510 ±29,2 (10) 155 Examined preparation (200) before p-CA 367 ±30,1 (10) 172 (40) before p-CA 228 ±18,9 (10) 107 F (4/44 28,94 (p<0,( D001) p-Chloramphetamine caused a decline of the cerebral se- rotonine concentration by 40%. Citalopram, applied before p-chloramphetamine, not only prevented the decline of the amine level, but caused its increase over the level of con¬ trol by 40%. The low dosage of the examined preparation did not produce any effects on the washing-out action of p-chloramphetamine. However, the high dosage prevented the p-chloramphetamine effect completely. 6) The effect on the process of learning and memorising. The effect was examined on rats by applying the model of learning accompanied by a jump on a bar with or without electroshock. The rats were taught the jump on a bar by means of conditioned (trained) impulse, which was a 1200 Hz frequency sound. The impulse lasted 8 seconds. After this the rats were treated with electric current at the voltage of 40V and frequency of 50Hz for the time of 12 seconds (unconditioned impulse) . Each of the animals received 10 i - pulse combinations daily in different time intervals (15-30 seconds) . The number of conditioned (trained) reactions (jumps on the bar) were measured in the examined and control groups. The preparations (the examined preparation in the dosage of 5 mg/kg, piraceta in the dosage of 100 mg/kg and pyritinol in the dosage of 100 mg/kg) were administered in- traperitoneally everyday, 60 minutes before the beginning of the experiment. The control animals received a physiological NaCl solution. It was observed that the examined preparation accelerates the process of learning. The effect is weaker than the effect of piracetam, but stronger than the effect of pyritinol. 7) The effect on the time of survival in the conditions of hypoxia. 20 mice, 18-20 g (10 animals were in the control group and 10 were administered the examined preparation) were put into two boxes with nitrogen-flow, whose concentration was being constantly increased (3 1/min) . The examined prepara¬ tion was applied i.o. in the dosages 5, 10, 50, 75, 100 mg/kg 60 minutes before the beginning of the experiment. The experiment lasted untill 0-3 animals survived in the control group. Subsequently oxygen was let in and finally normal air. The number of animals which survived in the control group was compared to the number of animals in the group ad- ministered the examined preparation. The results are presen¬ ted in Table 7. A number of surviving mice is presented in relation to the complete number of examined mice. The results were compared to those od piracetam and py¬ ritinol. It was observed thar the examined preparation, in comparison to piracetam and pyritinol, prolongs the time of mice survival in the conditions of hypoxia. Although the test is most frequently applied to the evaluation of nootro- pic substances, the same effect is demonstrated by prepara¬ tions of a very different profile of action, among others tranquilisers. Table . The number of mice surviving in the conditions of hypoxia n.nd. = not determined The reults of the pharmaceutical examinations give the evidence that the examined preparation has a very complex psychotropic activity, which can be ' defined as anti-depressive with a simultaneous depressive effect on the central nervous system (sedative component) . What demonstra¬ tes its anti-depressive action is the fact of a very conspi- cious decline of the beta-adrenergic receptor concentration, which is a characteristic effect of all anti-depressive pre- parations and procedures. It is also demonstrated by its in¬ hibiting effect on the uptake of noradrenaline or serotonin in vivo. Thirdly, its antidepressive effect is testified by the intensification of L-dopa effects in reserpine pretrea¬ ted mice and those premedicated with pargyline, as well as by shortening the immobility period in the animal model od depression (rats' depair test). The intensification of L-dopa effects suggests its anti-depressive and anti-parkinsonian activity. The nootro- pic characteristic of the examined preparation are demon- strated by its distinctively protecting action in the condi¬ tions of hypoxia and by improving the process of learning and memorising. The examined preparation may prove effective in the therapy of depression combined with hyperpraxia and nervosis with depressive component. Due to its nootropic action it may prove useful in the therapy of elderly. ■ The composition is presented in more detail in the fol¬ lowing examples, which are only illustrative and are not to be construed as limiting the scope of the invention in any way. Example 1. Tablets A tablet of the following composition was prepared (in grams) : 5-morpholinomethyl-3-(4-chlorobenzylideneamine)-2- oxazolidinone hydrochloride 0,05 Avicel (microcrystallic cellulose) 0,1073 Ethylcellulose (in the form of 5% anhydrous ethanol solution) 0,006 Talc 0,005 Magnesium stearate 0,0017 0,17 Example 2. Capsules Hard gelatine capsules were conventionally filled with 5-morpholinomethyl-3-(4-chlorobenzylideneamine)-2-oxazolidi- none hydrochloride in such a way that each capsule contained approximately 0,05 g of the active substance. Example 3 Dragees Tablets prepared as in Example 1 were covered in a coa¬ ting pan with a coat composed of saccharine, potato starch, talk, tragacanth and a coloring agent. Example 4. Injections The solution of the following composition was prepared (in grams) : 5-morpholinomethyl-3-(4-chlorobenzylideneamine)-2- oxazolidinone hydrochloride 1 Propylene glycol 49 Injection water 50 100 The solution was sterilised by means of a membrane fil¬ ter of 0,22 μm pore density and then it was poured into am¬ poules. Example 5. Injections The solution of the following composition was prepared (in grams) : 5-morpholinomethyl-3-(4-chlorobenzylideneamine)-2- oxazolidinone hydrochloride 1 Mannitol 1 Injection water 98 100 The solution was filtered by means of 0,22 μm density pore filter. Subsequently the solution was dosed into ampou¬ les, frozen in the temperature of approximately -30°C for 15-16 hours and finally freeze-dried for 24 hours. The final temperature was 30°C.

Claims: Claims 1. • A pharmaceutical composition, containing as active su¬ bstance 5-morpholino-3-(4-chlorobenzylideneamine)-2-oxazoli- dinone of formula I and/or pharmaceutically acceptable salt thereof together with pharmaceutically acceptable carriers and optionally au- xilliary agents. 2. A pharmaceutical composition according to claim 1, conta¬ ining as active substance 5-morpholino-3-(4-chlorobenzyli- deneamine)-2-oxazolidinone hydrochloride. 3. The use of 5-morpholino-3-(4-chlorobenzylideneamine)-2- oxazolidinone of formula I or pharmaceutically acceptable salt thereof for the preparation of a medicament having cen¬ tral nervous system activities. 4. A method of treatment of central nervous system diseases and disorders, comprising administering to a subject suf¬ fering from such disesase or disorder a therapeutically ef¬ fective amount of 5-morpholino-3-(4-chlorobenzylideneami- ne)-2-oxazolidinone of formula I or pharmaceutically accep¬ table salt thereof.

Inventors: BOGDAL MARIA, GRZESZKIEWICZ ANDRZEJ, KOBYLINSKA MARIA, KRZYWOSINSKI LESZEK, S CIR WIRSKA ALICJA, SERWIN-KRAJEWSKA MARTA, BOGDAL, MARIA, GRZESZKIEWICZ, ANDRZEJ, KOBYLINSKA, MARIA, KRZYWOSINSKI, LESZEK, S &CIR& WIRSKA, ALICJA, SERWIN-KRAJEWSKA, MARTA
Applicants: BOGDAL MARIA, GRZESZKIEWICZ ANDRZEJ, INST FARMACEUTYCZNY, KOBYLINSKA MARIA, KRZYWOSINSKI LESZEK, S & CIR & WIRSKA ALICJA, SERWIN KRAJEWSKA MARTA, BOGDAL, MARIA, GRZESZKIEWICZ, ANDRZEJ, INSTYTUT FARMACEUTYCZNY, KOBYLINSKA, MARIA, KRZYWOSINSKI, LESZEK, S &CIR& WIRSKA, ALICJA, SERWIN-KRAJEWSKA, MARTA
Application year: 1994
Main classification: A61K31
IPC codes: A61K31, A61P25, C07D263